Is HTR2A p.Arg393Trp (c.1177C>T) pathogenic?

HTR2A p.Arg393Trp (c.1177C>T) is classified Uncertain significance in HTR2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely pathogenic (0.7121); Very rare (popmax 0.00223%, eas).

How common is HTR2A p.Arg393Trp (c.1177C>T) in the general population?

HTR2A p.Arg393Trp (c.1177C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about HTR2A p.Arg393Trp (c.1177C>T)?

AlphaMissense predicts likely pathogenic (score 0.7121) — an in-silico prediction, not a clinical call.

HTR2A p.Arg393Trp

c.1177C>T · VCV4677298

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7121 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7121	likely pathogenic
REVEL	0.394	indeterminate
SaProt	LLR -16.76	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -0.061, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 83 bp · p 0.00029 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,898 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00105% 17/1,613,928 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,898
European (non-Finnish)	0.00127%	78,666
South Asian	0.0011%	91,086

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: HTR2A
Protein: p.Arg393Trp
Coding: c.1177C>T
MANE Select: NM_000621
Type: single nucleotide variant
Location: chr13:46835076 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 74.03 · 47 PDB
Residue 393: an α-helix

Full HTR2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HTR2A p.Ala447Val Likely benign ★★ same type
HTR2A p.Leu229= Benign/Likely benign ★★ same type
HTR2A p.Ser17= Benign ★★ same type
HTR2A p.Ser219= Likely benign ★★ same type
HTR2A p.Ser34= Likely benign ★★ same type
HTR2A p.Ser62= Likely benign ★★ same type
HTR2A c.412+1G>C Uncertain significance ★ same type
HTR2A p.Ala230Thr Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/htr2a-p-arg393trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown